The principal goals of this application are 1) to develop selective, potent analogues of lead anticancer beta-[unreadable] lactams that are highly effective in vitro and in vivo and 2) to create an effective learning experience for the[unreadable] minority students who participate in this research. The long-term goal is to identify one or more analogues for[unreadable] clinical evaluation. A need exists for new and novel anticancer agents with high potency, efficacy against[unreadable] malignant cell growth yet with reduced toxicity to non-cancerous cells. Toward this goal, studies of beta-lactams[unreadable] as new chemotherapeutic agents would be very timely and useful.[unreadable] A number of novel beta-lactams that have multicyclic aromatic groups have been synthesized. Some of them[unreadable] have demonstrated promising anticancer activity in vitro. In some instances this activity exceeded that of a[unreadable] well-known and clinically useful drug, cisplatin. In preliminary experiments one of these beta-lactams has shown[unreadable] anticancer activity in vivo against ovarian and colon cancer cell lines to a moderate degree. In an early[unreadable] search for the mechanism of action of these compounds, preliminary studies have demonstrated an[unreadable] extremely active blockade of the G2/M checkpoint in cancer cell lines.[unreadable] To identify the structural and mechanistic relationships and to more carefully identify selectivity of anticancer[unreadable] activity, an extended series of carefully designed beta-lactams analogues, related to lead compounds will be[unreadable] prepared. These include synthesis of racemic and optically active beta-lactams by Staudinger- and metal-mediated,[unreadable] and enolate condensation reactions. As an alternative approach, synthesis of these beta-lactams[unreadable] using domestic and automated microwave oven will also be performed. In vitro cytotoxicity will be utilized to[unreadable] determine the relative activity of these analogues and logical structural-stereochemical based pathway[unreadable] relationships will be explored to enhance their action. The ability of compounds to induce G2 cell cycle[unreadable] blockade for tests of mechanistic targets and efficacy will be investigated. In addition, their activity against[unreadable] DNA replication and induction of apoptosis will be studied. In a later aspect of the testing for the mechanism[unreadable] of action, a selected gene arrays designed to examine key elements of apoptosis will be accomplished. The[unreadable] same array will also be used to examine changes in genes known to be of importance in regulating the cell[unreadable] cycle.